Membrane association of α-synuclein (α-syn), a neuronal protein associated with Parkinson's disease (PD), is involved in α-syn function and pathology. Most previous studies on α-syn-membrane interactions have not used the physiologically relevant N-terminally acetylated (-acetyl) α-syn form nor the most naturally abundant cellular lipid, phosphatidylcholine (PC). Here, we report on how PC membrane fluidity affects the conformation and aggregation propensity of N-acetyl α-syn. It is well established that upon membrane binding, α-syn adopts an α-helical structure. Using CD spectroscopy, we show that N-acetyl α-syn transitions from α-helical to disordered at the lipid melting temperature ( ). We found that this fluidity sensing is a robust characteristic, unaffected by acyl chain length ( = 34-55 °C) and preserved in its homologs β- and γ-syn. Interestingly, both N-acetyl α-syn membrane binding and amyloid formation trended with lipid order (1,2-dipalmitoyl--glycero-3-phosphocholine (DPPC) > 1,2-dioleoyl--glycero-3-phosphocholine (DOPC)/sphingomyelin/cholesterol (2:2:1) ≥ DOPC), with gel-phase vesicles shortening aggregation kinetics and promoting fibril formation compared to fluid membranes. Furthermore, we found that acetylation enhances binding to PC micelles and small unilamellar vesicles with high curvature ( ∼16-20 nm) and that DPPC binding is reduced in the presence of cholesterol. These results confirmed that the exposure of hydrocarbon chains ( packing defects) is essential for binding to zwitterionic gel membranes. Collectively, our results suggest that N-acetyl α-syn localizes to highly curved, ordered membranes inside a cell. We propose that age-related changes in membrane fluidity can promote the formation of amyloid fibrils, insoluble materials associated with PD.

Amyloid formation is a pathological hallmark of many neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's. While it is unknown how these disorders are initiated, in vitro and cellular experiments confirm the importance of membranes. Ubiquitous in vivo, membranes induce conformational changes in amyloidogenic proteins and in some cases, facilitate aggregation. Reciprocally, perturbations in the bilayer structure can be induced by amyloid formation. Here, we review studies in the last 10 years describing α-synuclein (α-syn) and its interactions with membranes, detailing the roles of anionic and zwitterionic lipids in aggregation and their contribution to Parkinson's disease. We summarize the impact of α-syn α comparing monomeric, oligomeric, and fibrillar formson membrane structure, and the effect of membrane remodeling on amyloid formation. Finally, perspective on future studies investigating the interplay between α-syn aggregation and membranes are discussed. This article is part of a Special Issue entitled: Lipid-protein interactions in amyloid formation.

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